Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith

ABSTRACT

Described herein are injectable corticosteroid-loaded microparticles, pharmaceutical composition thereof and methods for reducing inflammation or pain in a body compartment such as a joint, an epidural space, a vitreous body of an eye, a surgically created space, or a space adjacent to an implant.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application Nos. 61/804,185, filed Mar. 21, 2013,which application is incorporated herein by reference in its entirety.

BACKGROUND

Technical Field

This disclosure relates to an injectable sustained release compositionand a method of delivery of the same to reduce inflammation and to treatpain in joints, including pain caused by inflammatory diseases such asosteoarthritis or rheumatoid arthritis.

Description of the Related Art

Arthritis i.e., inflammation in the joints, consists of more than 100different conditions which range from relatively mild forms oftendinitis and bursitis to crippling systemic forms, such as rheumatoidarthritis. It includes pain syndromes such as fibromyalgia andarthritis-related disorders, such as systemic lupus erythematosus, thatinvolve every part of the body.

Generally, there are two types of arthritis:

-   -   Rheumatoid arthritis (“RA”) and related diseases, which are        immune-mediated systemic inflammatory joint diseases.    -   Osteoarthritis (“OA”), which is a degenerative joint disease,        the onset of which is typically mediated by previous joint        injury or other factors.

The common denominator for all of these arthritic conditions, includingRA and OA is joint and musculoskeletal pain. Often this pain is a resultof inflammation of the joint lining which is the body's natural responseto injury. Such inflammation and pain can prevent the normal use andfunction of the joint. Pain and disability from arthritis, jointdegeneration, and surgery are generally treated by a combination of oralmedications or intra-articular injections of steroid compounds designedto reduce inflammation. In addition, other compositions, such ashyaluronic acid products, have been injected to providevisco-supplementation. A distinct benefit of a corticosteroid injectionis that the relief of localized inflammation in a particular body areais more rapid and powerful than what can be achieved with traditionalanti-inflammatory oral medications, such as aspirin. A single injectionalso can avoid certain side effects that can accompany multiple doses oforal anti-inflammatory medications, notably irritation of the stomach.Injections can be administered easily in a doctor's office. Otheradvantages include the rapid onset of the medication's action.Unfortunately, injections also have some systemic side effects or arenot effective for extended periods of time.

Short-term complications are uncommon. Long-term risks of corticosteroidinjections depend on the dose and frequency of the injections. Withhigher doses and frequent administration, potential side effects includethinning of the skin, easy bruising, weight gain, puffiness of the face,acne (steroid acne), elevation of blood pressure, cataract formation,thinning of the bones (osteoporosis), and a rare but serious type ofdamage to the bones of the large joints (avascular necrosis).Furthermore, there is an interdependent feedback mechanism between thehypothalamus, which is responsible for secretion ofcorticotrophin-releasing factor, the pituitary gland, which isresponsible for secretion of adrenocorticotropic hormone, and theadrenal cortex, which secretes cortisol, termed thehypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may besuppressed by the administration of corticosteroids, leading to avariety of unwanted side effects.

Accordingly, there is a medical need to extend the local duration ofaction of corticosteroids, while reducing the systemic side effectsassociated with that administration. In addition, there is a need forsustained local treatment of pain and inflammation, such as joint pain,with corticosteroids that results in clinically insignificant or nomeasurable HPA axis suppression. In addition, there is a medical need toslow, arrest, reverse or otherwise inhibit structural damage to tissuescaused by inflammatory diseases such as damage to articular tissuesresulting from osteoarthritis or rheumatoid arthritis.

BRIEF SUMMARY

Described herein are pharmaceutical compositions, injectable dosageforms and method of using the same for treating inflammation and/ormanage pain in a body compartment, such as a joint space, an epiduralspace, a vitreous body of an eye, a surgically created space, or a spaceadjacent to an implant.

One embodiment provides a pharmaceutical composition, comprising: aplurality of microparticles, the microparticle including: (1) acrystalline drug core of more than 70% by weight of the microparticle,the crystalline drug core including one or more crystals of fluticasoneor a pharmaceutically acceptable salt or ester thereof; and (2) apolymeric shell encapsulating the crystalline drug core, the polymericshell being in contact but immiscible with the crystalline drug core,wherein said microparticles when dissolution tested using United StatesPharmacopoeia Type II apparatus exhibit a dissolution half-life of 12-20hours, wherein the dissolution conditions are: 3 milligrams ofmicroparticles in 200 milliliters of dissolution medium of 70% v/vmethanol and 30% v/v of water at 25° C.

A further embodiment provides a pharmaceutical composition, comprising:a plurality of microparticles, the microparticle including: (1) acrystalline drug core of more than 70% by weight of the microparticle,the crystalline drug core including one or more crystals of fluticasoneor a pharmaceutically acceptable salt or ester thereof; and (2) apolymeric shell encapsulating the crystalline drug core, the polymericshell being in contact but immiscible with the crystalline drug core,wherein the microparticles are heat treated within a temperature rangeof 210-230° C. for at least one hour.

Yet another embodiment provides a unit dosage form of a corticosteroidfor injecting into a body compartment, comprising: a plurality ofmicroparticles, the microparticle including: (1) a crystalline drug coreof more than 70% by weight of the microparticle; and (2) a polymericshell encapsulating the crystalline drug core, wherein the crystallinedrug core includes one or more crystals of a corticosteroid selectedfrom fluticasone, fluticasone furoate, and fluticasone propionate, andthe polymeric shell is in contact but immiscible with the crystallinedrug core, wherein the unit dosage form is capable of sustained-releaseof the corticosteroid over a period of 2-12 months while maintaining aminimum therapeutically effective concentration of the corticosteroidwithin the body compartment.

Yet a further embodiment provides a method of decreasing inflammation ormanaging pain in a patient in need thereof comprising administering tothe patient, via injection to a body compartment, a therapeuticallyeffective amount of a pharmaceutical composition for sustained releaseof a corticosteroid wherein the pharmaceutical composition comprises aplurality of microparticles and a pharmaceutically acceptable vehicle,the microparticle including: (1) a crystalline drug core of more than70% by weight of the microparticle; and (2) a polymeric shellencapsulating the crystalline drug core, and wherein the crystallinedrug core includes one or more crystals of fluticasone or apharmaceutically acceptable salt or ester thereof, and the polymericshell is in contact but immiscible with the crystalline drug core.

A further embodiment provides a method for forming coatedmicroparticles, comprising: providing a crystalline drug core includingone or more crystals of a corticosteroid, forming a polymeric shell bycoating one or more coats of a polymeric solution having a biodegradablepolymer and a solvent; allowing the solvent to dry to provide coatedmicroparticles; and heating the coated microparticles at 210-230° C. forat least one hour.

Yet another embodiment provides a method of decreasing inflammation ormanaging pain in a patient in need thereof comprising: administering tothe patient, via a single injection to a body compartment, a unit dosageform for sustained release of a corticosteroid wherein the unit dosageform comprises a plurality of microparticles and a pharmaceuticallyacceptable vehicle, wherein the crystalline drug core includes one ormore crystals of a corticosteroid selected from fluticasone, fluticasonefuroate, and fluticasone propionate, and the polymeric shell is incontact but immiscible with the crystalline drug core, and wherein,following the single injection, the corticosteroid is released over aperiod of 2-12 months while maintaining a minimum therapeuticallyeffective concentration of the corticosteroid within the bodycompartment.

The present disclosure further provides a corticosteroid which isadministered locally as a sustained release dosage form (with or withoutan immediate release component) that results in efficacy accompanied byclinically insignificant or no measurable effect on endogenous cortisolproduction.

The present disclosure further provides a membrane based,diffusion-driven release mechanism with drug particle sizing largeenough to allow high drug loading, but small enough to be injectedintra-articularly.

The present disclosure further provides a use of an intra-articularlyinjected, therapeutically effective amount of a pharmaceuticalpreparation for sustained release of a corticosteroid selected from thegroup consisting of fluticasone, fluticasone furoate, and fluticasonepropionate, comprising a multiplicity of coated microparticles, saidcoated microparticles having a mean diameter in a range of 50 μm to 400μm and wherein the microparticles are particles comprised of greaterthan 70% corticosteroid by weight, to decrease inflammation and toreduce pain in a patient.

As provided herein, corticosteroids (“drug” or “therapeutic agent”) arecoated with a semi-permeable polymeric shell and injected into thejoint. Water then diffuses through the polymer and dissolves the drugcore (D) creating a saturated solution inside the membrane (C) andessentially sink conditions outside the particle (c). This concentrationgradient drives a constant (zero order) release of drug from the drugparticle as long as there is some drug core remaining to maintain asaturated solution. The period of release can be tuned by altering thepermeability of the polymer coating.

The present disclosure further relates to the delivery of compositionsto reduce inflammation and to treat pain in joints, including paincaused by inflammatory diseases such as osteoarthritis or rheumatoidarthritis and to slow, arrest or reverse structural damage to tissuescaused by an inflammatory disease, for example damage to articularand/or peri-articular tissues caused by osteoarthritis or rheumatoidarthritis.

By way of the method of the present disclosure, there is provided ameans to reduce morbidity due to arthritis by employing andadministering to a patient a long-lasting injectable, intra-articulardrug delivery composition. While intra-articular steroids have been amainstay of treatment for arthritis for more than 50 years, for manypatients, multiple steroid injections are necessary with attendant risksand side effects. There is provided herein a platform and method toovercome these side effects via a sustained release delivery method,which can provide pseudo-zero order release, without an initial burst,on the order of months for low solubility steroids. An intra-articularinjectable formulation for this use and with these properties has neverbeen described in the literature.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The following figures set forth embodiments in which like referencenumerals denote like parts. Embodiments are illustrated by way ofexample and not by way of limitation in all of the accompanying figureswherein:

FIG. 1 shows schematically a microparticle of core/shell morphology.

FIG. 2 shows the in vitro release profiles of fluticasone propionate asuncoated powder, uncoated crystal and coated crystal.

FIG. 3A shows the release profiles of fluticasone propionatemicroparticles having undergone heat-treatment at various temperatures.

FIG. 3B shows the release half-lives of fluticasone propionatemicroparticles having undergone heat-treatment at various temperatures.

FIGS. 4A and 4B show the particle size distribution of the fluticasonepropionate microparticles as compared to particle size distribution oftriamcinolone hexacetonide (TA) (Kenalog™).

FIG. 5 is a graph showing the relative amounts of fluticasone propionateand PVA in microparticles by ¹H NMR analysis.

FIG. 6 is a graph showing dissolution profiles of triamcinolonehexacetonide (TA) as compared to sustained release (SR) formulations offluticasone propionate (FP) according to embodiments of this disclosure.

FIG. 7 is a graph showing plasma fluticasone (FP) levels, synovial fluidFP levels after injection of 20 mg formulation into knee joint of sheepas compared to intra-articular pharmacokinetics of triamcinolonehexacetonide (40 mg) from human subjects.

FIGS. 8A, 8B and 8C demonstrate the results of a histologicalexamination of the injected joints of sheep showing no abnormalities.

FIG. 9 shows the local concentrations in tissue and synovial fluid ofknee joints of dogs for a period of 60 days following a single injectionof a low dose fluticasone propionate. The plasma concentrations were toolow to detect.

FIG. 10 shows the local concentrations in tissue and synovial fluid ofknee joints of dogs, as well as the plasma concentrations, for a periodof 60 days following a single injection of a high dose fluticasonepropionate.

FIG. 11 shows the plasma concentrations of fluticasone propionatefollowing injections to the knee joints of sheep as compared to those ofdogs. The microparticles for each injection had undergone differentheat-treatments prior to being formulated into injectable compositions.

FIG. 12 shows the plasma concentrations of fluticasone propionate in theknee joints of dogs over a period of 45 hours following a singleinjection. The pharmacokinetic (PK) curve indicates a lack of initialburst.

DETAILED DESCRIPTION

Described herein are pharmaceutical compositions, injectable dosageforms and method of using the same for treating inflammation and/ormanage pain in a body compartment, such as a joint space, an epiduralspace, a vitreous body of an eye, a surgically created space, or a spaceadjacent to an implant. The pharmaceutical composition includes aplurality of microparticles in core/shell morphology. In particular, themicroparticle includes a crystalline drug core of a corticosteroid and apolymeric shell encapsulating the crystalline drug core. As discussed infurther detail herein, the injectable microparticles are characterizedwith high drug-loading, narrow size distribution and a sustained releaseprofile of pseudo zero-order release over a period of 2-12 months withina body compartment, e.g., a joint.

Several studies have confirmed that the efficacy of intra-articularcorticosteroids is directly related to their intra-articular residencetime. Caldwell J R. Intra-articular corticosteroids. Guide to selectionand indications for use. Drugs 52(4):507-514, 1996. It has beensurprisingly found that when a direct injection of the pharmaceuticalcomposition or dosage form is made to a body compartment, e.g., anintra-articular space, an epidural space or within the vitreous of theeye, there is an unexpected, long-term sustained release of thecorticosteroid with minimal systemic impact.

The sustained release delivery mechanism is based on dissolution. Whilenot wishing to be bound by any specific mechanism of action, it has beenfound that when crystalline corticosteroid drug particles coated withsemi-permeable polymeric shells are injected into a body compartment,e.g., intra-articularly, water from the body compartment diffusesthrough the polymeric shell and partially dissolves the crystal drugcore. As a result, a saturated solution of the drug is formed inside thepolymeric shell. Since there are essentially sink conditions in thefluid (e.g., synovia when the body compartment is a joint) in which themicroparticles are injected and reside, a concentration gradient iscreated which continuously drives the corticosteroid drug out of themicroparticles and into the surrounding fluid. As long as there is somedrug core remaining to maintain a saturated solution within thepolymeric shell, a constant (i.e., zero order or pseudo-zero order)release of the drug from the coated microparticles is obtained.

Also disclosed herein is a method for reducing inflammation or managingpain, e.g. due to arthritis, by administering an injectable dosage formto a body compartment (e.g., intra-articular injection). Advantageously,the release is highly localized within the local tissue or fluid mediumof the body compartment (e.g., synovium of synovial fluid) to ensure along-acting local therapeutic level, while maintaining a low orundetectable systemic level of the corticosteroid.

Definitions

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “plurality” means “two or more”, unless expressly specifiedotherwise. For example, “plurality” may simply refer to a multiplicityof microparticles (two or more) or an entire population ofmicroparticles in a given composition or dosage form, e.g., for purposeof calculating the size distribution of the microparticles.

As used herein, unless specifically indicated otherwise, the word “or”means “either/or,” but is not limited to “either/or.” Instead, “or” mayalso mean “and/or.”

When used with respect to a therapeutic agent or a drug (e.g., acorticosteroids), the terms “sustained release” or “extended release”are used interchangeably. Sustained release refers to continuouslyreleasing the therapeutic agent over an extended period of time afteradministration of a single dose, thus providing a prolonged therapeuticeffect throughout the release period.

“Sustained release” is in contrast to a bolus type administration inwhich the entire amount of the active agent/substance is madebiologically available at one time. Nevertheless, “sustained release”may include an initial faster release followed by a longer, extendedperiod of slower release. As discussed in further detail below, theconstruction of the microparticles makes it possible to minimize theinitial faster release (e.g., a burst release) and prolong the extendedrelease period to achieve a profile of near constant release that isirrespective of the drug concentration (i.e., a zero-order or pseudozero-order release).

Not all non-zero release is within the meaning of “sustained release.”Rather, “sustained release” should provide at least a minimumtherapeutically effective amount (as defined herein) of thecorticosteroids during the release period. It should be understood thatthe minimum therapeutically effective amount of corticosteroid dependson the severity of the inflammation and/or pain to be addressed.

“Sustained release period” refers to the entire period of release duringwhich a local concentration of the corticosteroid drug is maintained ator above a minimum therapeutically effective amount. The desiredsustained-release period can, of course, vary with the disease orcondition being treated, the nature of the corticosteroid, and thecondition of the particular patient to be treated. Thus, the desiredsustained-release period can be determined by the attending physician.

“Local concentration” refers to the concentration of the corticosteroiddrug within a body compartment (as defined herein), including theconcentration in the tissue or fluid of the body compartment.

“Plasma concentration” refers to the concentration of the corticosteroiddrug in the plasma or serum. The injectable microparticles are capableof highly localized release during a prolonged period while maintaininga low plasma concentration, e.g., sufficiently low to minimize HPA axissuppression during the sustained release period. Plasma concentrationbelow 75 pg/mL is considered below quantifiable limits (BQL), below 30pg/mL is considered undetectable.

Within the scope of the present disclosure, sustained release of thecorticosteroid is achieved due to the unique structure of themicroparticles, which are in core/shell morphology. In particular, acrystalline drug core of a corticosteroid is encapsulated by a polymericshell composed of one or more polymeric coatings, each permeable to thecorticosteroid. In a preferred embodiment, all layers comprise the samepolymer. In other embodiments, two to four layers of the polymer arecoated on the corticosteroid, with each layer incrementally slowing therelease of the active ingredient and collectively providing the desiredsustained release. Furthermore, sustained release of the corticosteroidis achieved by tailoring this delivery platform to the aqueous or sinkenvironment of the body compartment (e.g., synovium).

As used herein, a “patient,” or “subject,” to be treated by the methodsaccording to various embodiments may mean either a human or a non-humananimal, such as primates, mammals, and vertebrates.

The phrase “therapeutically effective amount” refers to an amount of atherapeutic agent that, when delivered to a body compartment (e.g.,intra-articularly) in the form of the coated microparticles as definedherein, produces a degree of reduced inflammation or pain in the bodycompartment (e.g., a joint) in a patient (at a reasonable benefit/riskratio applicable to any medical treatment). The effective amount of thetherapeutic agent may vary depending on such factors as the type andseverity of arthritis being treated, its advancement, the degree of painto which patient is subject, the particular microparticle beingadministered, the active agent and/or the size/age/gender of thesubject. One of ordinary skill in the art may empirically determine theeffective amount of a particular therapeutic agent according to knownmethods in the art. Unless specified otherwise, “therapeuticallyeffective amount” refers to the amount of the therapeutic agentlocalized within the body compartment.

“Minimum therapeutically effective amount” is the least amount of thetherapeutic agent that is capable of producing a therapeutic effect(e.g., pain reduction or anti-inflammation).

“EC50” is the concentration of the therapeutic agent that provides 50%of the maximal effect, e.g., in reducing inflammation or pain.

“Unit dosage form” refers to physically discrete units (e.g., loadedsyringe cylinders) suitable as unitary dosages for human subjects, eachunit containing a predetermined quantity of the therapeutic agent inassociation with a pharmaceutical acceptable vehicle. The quantity ofthe therapeutic agent is calculated to produce the desired therapeuticeffect for a desired period of time.

The term “treating” is art-recognized and includes treating the diseaseor condition by ameliorating at least one symptom of the particulardisease or condition, even if the underlying pathophysiology is notaffected.

“Body compartment” refers to a space or cavity within the body of avertebrate (including human) that is accessible by injection. Typically,the body compartment is at least semi-enclosed or fully enclosed by hardor soft tissue (e.g., bones, membranes, ligamentous structure) thatdefines the space. Soft tissue is typically present and may have variousdegrees of vascularization. The body compartment typically contains afluid, such as the synovial fluid in the joints, spinal fluid in theepidural and the vitreous humour in the vitreous body of the eye. Thefluid may or may not communicate with the outside of the bodycompartment. More specifically, the body compartment may be naturallyoccurring anatomical space such as a synovial joint, an epidural spaceor a vitreous body of an eye. In addition, the body compartment may alsobe a surgically created space (e.g., a pocket for inserting an implanteddevice, soft tissue implant such as breast implant, and the like) or anyspace near the implant that can be accessed through injection.

The term “synovial joint” refers to a moveable articulation of two ormore bones. The articulation is defined by a synovial cavity, whichcontains a volume of synovial fluid, is lined with a synovial membrane,and is surrounded by a fibrous capsule. The opposing bone surfaces areeach covered with a layer of cartilage. The cartilage and synovial fluidreduce friction between the articulating bone surfaces and enable smoothmovements. Synovial joints can be further distinguished by their shape,which controls the movements they allow. For example, hinge joints actlike the hinge on a door, allowing flexion and extension in just oneplane. An example is the elbow between the humerus and the ulna. Balland socket joints, such as the hip, allow movement in several planessimultaneously. Condyloid (or ellipsoid) joints, such as the knee,permit motion in more than one plane in some positions but not others.For example, no rotation is possible in the extended knee, but somerotation is possible when the knee is flexed. Pivot joints, such as theelbow (between the radius and the ulna), allow one bone to rotate aroundanother. Saddle joints, such as at the thumb (between the metacarpal andcarpal) are so named because of their saddle shape, and allow movementin a variety of directions. Finally, gliding joints, such as in thecarpals of the wrist, allow a wide variety of movement, but not muchdistance.

Synovial joints include, but are not limited to, shoulder (glenohumeraland acromioclavicular), elbow (ulno-humeral, radio-capitellar andproximal radioulnar), forearm (radioulnar, radiocarpal, ulnocarpal),wrist (distal radioulnar, radio-carpal, ulno-carpal, mid carpal), hand(carpo-metacarpal, metocarpophalangeal, interphalangeal), spine(intervertebral), hip, knee, ankle (tibiotalar, tibiofibular), and foot(talocalcaneal, talonavicular, intertarsal, tarso-metatarsal,metatarsal-phalangeal, interphalangeal).

“Intra-ocular” and “intravitreous” are used herein interchangeably tomean within the vitreous humour of the eye.

As used herein, the term “microparticle” means a particle having meandimension less than 1 mm. Although the microparticles are substantiallyspherical in some embodiments, the microparticles can be any solidgeometric shape which is not inconsistent with the principles of thedisclosure, including, without limitation, needles, ellipsoids,cylinders, polyhedrons and irregular shapes.

Microparticles are coated crystalline drug particles. As used herein, amicroparticle has a “core/shell” morphology, shown schematically in FIG.1, in which the drug core (10) is encapsulated by a polymeric shell(20), the polymeric shell may include one or more thin coatings of thesame or different polymers (two coatings, 25 and 30, are shown).Importantly, the polymeric shell (20) is formed of polymer coatings thatare not miscible with the drug core, thus, the interface (40) betweenthe drug core and the polymeric shell is sharp with minimal amounts ofdrug or polymer (e.g., less than 5%, or less than 1% or less than 0.5%of the total weight of either the drug or polymer shall be mixed).Because the drug core contains a highly hydrophobic corticosteroid drug,the polymeric shell includes at least one hydrophilic polymer. Althoughthe polymeric shell may be ultimately degraded, it should maintain itsstructural integrity throughout the sustained release period, thusretaining an environment for the dissolving drug core to form asaturated solution.

As used herein, the term “active pharmaceutical ingredient,”“therapeutic agent,” or drug, means one or more corticosteroids. As usedherein, corticosteroid means fluticasone or a pharmaceuticallyacceptable salt or ester thereof. More specifically, the corticosteroidmay be at least one of fluticasone, fluticasone furoate, and fluticasonepropionate, derivatives, or pharmaceutically acceptable salts or estersthereof.

As used herein, the terms “crystalline drug core,” “core particle,” and“drug core” interchangeably refer to a pre-formed particle that includesa single crystal or multiple crystals of the drug. The drug core isencapsulated by a polymeric shell. The core particle can furthercomprise other compounds, including, without limitation, binders,buffers, antioxidants, excipients, and additional active pharmaceuticalingredients. The core particle can be a single large crystal, amultiplicity of crystals, or mixtures of the above. In a preferredembodiment, the drug core is substantially pure drug (i.e., at least90%, or at least 95% or at least 98% of the entire weight of the drugcore is the drug). In a preferred embodiment, the drug core is 100%crystalline drug.

As used herein, “polymeric shell” includes one or more polymericcoatings. “Polymeric coating” means a thin layer of linear, branched orcross-linked macromolecules that has a continuous surface surroundingthe crystalline drug core. Referring to FIG. 1, the polymeric coatings(25 and 30) are sequentially and concentrically coated on the drug core(20). Although the drug core (20) and the immediate adjacent polymericcoating (25) should be immiscible, the polymeric coatings (25 and 30)themselves may be in intimate contact with each other, allowing forcertain degrees of miscibility at the interface (50) between adjacentcoatings in order to form a polymeric shell (20) of a cohesive structurethat affords structural integrity during the sustained release period.The polymeric shell must substantially surround or envelope the coreparticles.

“Coating solution” refers to a solution of pre-formed polymers (e.g.,commercially available polymers) and is suitable for coating the drugcore according to known methods of the art, e.g. fluidized bed coating.

As used herein, the term “permeable” means allowing the passage ofmolecules of the therapeutic agent by diffusion but not by fluid flow.

As used herein, the term “semi-permeable” means permeable to somemolecules but not to others. As used herein, semi-permeable polymericshell are permeable to at least water and the therapeutic agent withinthe coated microparticles of the disclosure.

“Dissolution half-life” is an in vitro measurement of the dissolutioncharacteristics of the microparticles. Specifically, the dissolutionhalf-life is the amount of time that is taken for half of the originalloading of the drug in the microparticles to dissolve and release into adissolution medium under a specific set of dissolution conditions.Although carried out in vitro, the dissolution half-life is neverthelessan art-recognized factor to consider in predicting in vivo releasecharacteristics and can represent an accelerated model of the sustainedrelease behavior in vivo. In particular, dissolution half-life providesa qualitative tool for predicting in vivo behaviors by comparing thedissolutions half-lives of various formulations. For instance,formulations that exhibit a longer dissolution half-life in vitro areexpected to exhibit a longer sustained release period in vivo. Unlessspecified otherwise, the dissolution system used for measuringdissolution half-life the microparticles is USP Type II (paddle).

“Dissolution profile” is a graphic representation of the percentagedissolution as measured by time. Besides providing quantitatively thedissolution amount as a function of time, the curvature of the profilequalitatively shows the extent of the initial burst. For example, asharp rise in the curvature indicates a faster initial release (burst)when compared with a gentler rise.

“Vehicle” refers to a non-toxic carrier, adjuvant, or solvent into whichthe microparticles are suspended. The vehicle does not alter or destroythe pharmacological activity of the therapeutic agent with which it isformulated. Pharmaceutically acceptable carriers or vehicles that may beused in the compositions include, but are not limited to, water,physiological saline, hyaluronic acid, and the like. As used herein, theterm “biocompatible” means characterized by not causing a toxic,injurious or immunological response when brought into contact withliving tissue, particularly human or other mammalian tissue.

As used herein, the term “biodegradable” means capable of partially orcompletely dissolving or decomposing in living tissue, particularlyhuman or other mammalian tissue. Biodegradable compounds can be degradedby any mechanism, including, without limitation, hydrolysis, catalysisand enzymatic action.

As used herein with respect to polymeric coatings, the term“substantially degraded” means degraded to the degree that approximately50% of the chemical bonds resulting from polymerization of thepolymer-forming solution to form the polymeric coating have been broken.

As used herein with respect to the polymeric shell of the disclosure,the term “structural integrity” means retaining a continuous surfacewhich is semi-permeable and permits diffusion, but does not include anydiscontinuities which permit fluid flow.

As used herein, the term “external environment” means the local area orregion of tissue surrounding the coated microparticles of the disclosureafter direct injection into the body compartment.

As used herein, the term “saturated” means containing the maximumconcentration of a solute (e.g., an active pharmaceutical ingredient)that can be dissolved at a given temperature.

As used herein, the term “substantially insoluble” means having asolubility of less than 1 part solute per 1000 parts solvent by weight.

As used herein, the term “hydrophobic” means having lower affinity foran aqueous solvent than an organic solvent.

As used herein, the term “hydrophilic” means having lower affinity foran organic solvent than an aqueous solvent.

As used herein, term “pseudo-zero-order kinetics” meanssustained-release of the active pharmaceutical ingredient(corticosteroid) which exhibits kinetics which is zero-order (i.e.,independent of concentration) or between zero-order and first-order(i.e., proportional to concentration) kinetics over thesustained-release period, where the concentration is based on the totalamount of the active pharmaceutical ingredient contained within thecoated microparticles. In some embodiments, the release of the activepharmaceutical ingredient exhibits kinetics which more closelyapproximate zero-order than first-order kinetics.

As used herein, the recitation of a numerical range for a variable isintended to convey that the disclosure may be practiced with thevariable equal to any of the values within that range. Thus, for avariable which is inherently discrete, the variable can be equal to anyinteger value within the numerical range, including the end-points ofthe range. Similarly, for a variable which is inherently continuous, thevariable can be equal to any real value within the numerical range,including the end-points of the range. As an example, and withoutlimitation, a variable which is described as having values between 0 and2 can take the values 0, 1 or 2 if the variable is inherently discrete,and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values0 and if the variable is inherently continuous.

Microparticles

The microparticles of the core/shell morphology described herein areconstructed to exhibit a sustained release profile uniquely suited forhighly localized, extended delivery of a corticosteroid drug within abody compartment. In particular, the microparticle includes (1) acrystalline drug core of more than 70% by weight of the microparticle,wherein the crystalline drug core includes one or more crystals offluticasone or a pharmaceutically acceptable salt or ester thereof; and(2) a polymeric shell encapsulating the crystalline drug core, wherebythe polymeric shell is in contact but immiscible with the crystallinedrug core.

The in vivo sustained release profile is correlatable to the in vitrodissolution characteristics of the microparticles, which in turn aredetermined by, among others, the solubility of the drug core, thepermeability, the level of crosslinking and the rate of degradation ofthe polymeric shell. Due to a precision heat-treatment step in theformation, the microparticles described herein unexpectedly have a longdissolution half-life of 12-20 hours, when tested using United StatesPharmacopoeia Type II apparatus wherein the dissolution conditions are 3milligrams of microparticles in 200 milliliters of dissolution medium of70% v/v methanol and 30% v/v of water at 25° C. These features arediscussed in more detail below.

Crystalline Drug Core

The crystalline drug core according to the embodiments of thisdisclosure is a corticosteroid drug. More specifically, the crystallinedrug core comprises at least one of fluticasone, or a pharmaceuticallyacceptable salt or ester thereof. More specifically, the core comprisesat least one of fluticasone, fluticasone furoate, and fluticasonepropionate. Most preferably, the corticosteroid is fluticasonepropionate.

As the preferred system is for formulating corticosteroids, and as thisis a “dissolution based delivery system,” corticosteroids of relativelow solubility are preferred. Fluticasone in general and fluticasonepropionate in particular are ideal in this regard due to potency andhigh degree of insolubility. Johnson M. Development of fluticasonepropionate and comparison with other inhaled corticosteroids. TheJournal of allergy and clinical immunology 101(4 Pt 2):S434-9, 1998.

The crystalline form of the corticosteroid drug has even lowersolubility than the amorphous form of the same drug, resulting in alonger dissolution half-life and less initial burst. Accordingly, thedrug core may be a single large crystal or an aggregation of multiplesmall crystals. Crystalline drug core coated with a polymeric shellfurther extends the period of dissolution and further minimizes anyinitial burst.

The exact anti-inflammatory mechanism of action of corticosteroids isunknown. However, it is well known that steroids have many potentiallyanti-inflammatory actions, and they inhibit the expression and action ofmany proinflammatory cytokines. Brattsand R, et al. Cytokine modulationby glucocorticoids: mechanisms and actions in cellular studies.Alimentary Pharmacology & Therapeutics 2:81-90, 1996. Glucocorticoidsmodulate cytokine expression by a complex combination of genomicmechanisms, and the activated glucocorticoid receptor complex can bindto and inactivate key pro inflammatory transcript factors. In addition,inflammation can be suppressed via glucocorticoid responsive elements(GRE) which up-regulate the expression of cytokine inhibitory proteins.In studies with triggered human blood mononuclear cells in culture,glucocorticoids strongly diminished production of the initial phasecytokines IL-1 beta and TNF alpha, immunomodulatory cytokines IL-2,IL-3, IL-4, IL-6 IL-10, IL-12 and INF gamma, as well as IL-6, IL-8 andthe growth factor GM-CSF. Cato A C et al. Molecular mechanisms ofanti-inflammatory action of glucocorticoids. Biochemical SocietyTransactions 18(5):371-378, 1996. In addition to diminishing theproduction of cytokine, steroids can also inhibit its subsequentactions. Because cytokines work in cascades, this means that steroidtreatment can block expression of the subsequent cytokines. This blockedcytokine activity does not depend on a reduced cytokine receptorexpression, but may be associated with receptor up regulation. Jusko WJ. Pharmacokinetics and receptor-mediated pharmacodynamics ofcorticosteroids. Toxicology 102(1-2):189-196, 1995.

The therapeutic agents are used in amounts that are therapeuticallyeffective, which varies widely depending largely on the particular agentbeing used. The amount of agent incorporated into the composition alsodepends upon the desired release profile, the concentration of the agentrequired for a biological effect, and the length of time that thebiologically active substance has to be released for treatment.

There is no critical upper limit on the amount of therapeutic agentincorporated except for that of an acceptable solution or dispersionviscosity to maintain the physical characteristics desired for thecomposition. The lower limit of the agent incorporated into the polymersystem is dependent upon the activity of the corticosteroid and thelength of time needed for treatment. Thus, the amount of thecorticosteroid should not be so small that it fails to produce thedesired physiological effect, nor so large that it is released in anuncontrollable manner.

A key advantage of the injectable microparticles lies in the much higherdrug loading than previously known drug-loaded microparticles. In otherwords, each microparticle has a comparatively and significantly smallerfraction as the polymeric shell, and a comparatively and significantlygreater fraction as the corticosteroid core.

Moreover, the drug core is substantially pure drug as the drug core isprepared from recrystallized drug in the form of either a single largecrystal or an aggregate of smaller crystals. Thus, “substantially pure”means at least 90%, or at least 95% or at least 98%, or 100% of theentire weight of the drug core is the drug in a crystalline form.

Thus, in various embodiments, in each microparticle, 70-97% of the totalweight of microparticle is corticosteroid and 3-30% is polymer. In oneembodiment, the drug core is more than 70% of the total weight of themicroparticle and less than 30% of the total weight of the microparticleis the polymeric shell. In other embodiments, the drug core is more than75%, more than 80%, more than 85%, more than 90% or more than 95% of thetotal weight of the microparticle, with the remainder of themicroparticle being the polymeric shell.

Polymeric Shell

The polymeric shell comprises one or more concentrically orconsecutively coated polymeric coatings of the same or differentpolymers. Standard biocompatible and biodegradable polymeric coatingsknown in the art can be employed to the extent that they meet therequirements described above with respect to retaining permeabilityand/or structural integrity during the desired sustained-release period.While the sustained release period is enhanced within the scope of thedisclosure via higher drug loading and the beneficial and unexpectedinteraction of the body compartment (e.g., synovial environment) and thedissolution-based delivery system described herein, there are additionalfactors at play supporting the superior efficacy of the method hereinincluding, but not limited to:

-   -   the degree of solubility of the corticosteroid    -   the rate of clearance of the corticosteroid from the synovium    -   the size of the core particle and/or the amount of the        corticosteroid initially present in the core particle    -   the presence of other compounds within the core particle that        affect the rate of release of the corticosteroid    -   the permeability of the polymeric coating(s) to the        corticosteroid    -   the rate of degradation of the polymeric coating(s), as well as        other factors.

As is known in the art, both the permeability and biodegradability ofpolymeric coatings can be affected by the choice of polymeric material(e.g., degree of hydrophobicity or hydrophilicity relative to thecorticosteroid; degree of lability of bonds under physiologicalconditions), degree of cross-linking and thickness. For co-polymers, theratio of the different monomers also can be varied to affectpermeability and biodegradability.

In preferred embodiments, suitable biocompatible and biodegradablepolymers include polyvinyl alcohol (PVA), poly(p-xylylene) polymers(trademarked as Parylene®), poly(lactic acid) (PLA), poly(glycolic acid)(PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL),poly(valerolactone) (PVL), poly(ε-decalactone) (PDL),poly(1,4-dioxane-2,3-dione), poly(1,3-dioxane-2-one),poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB),poly(hydroxyvaleric acid) (PHV), ethylene vinyl acetate (EVA) andpoly(β-malic acid) (PMLA).

In order to affect permeability and release rates, the polymericcoatings can optionally be covalently or ionically cross-linked. Forexample, monomers can be chosen which include chemical groups which arecapable of forming additional bonds between monomers, or separatecross-linking agents can be included in the polymer-forming solutions inaddition to the monomers. In some embodiments, the cross-linking groupsare thermally activated, whereas in other embodiments they arephotoactivated, including photoactivation by visible or ultravioletradiation. Cross-linking groups include, without limitation, unsaturatedgroups such as vinyl, allyl, cinnamate, acrylate, diacrylate,oligoacrylate, methacrylate, dimethacrylate, and oligomethoacrylategroups. As many corticosteroids are hydrophobic, and because it isdesirable to reduce or avoid dissolution of the drug core into thepolymeric shell in order to maintain a sharp interface between the coreand shell, the polymeric shell should include a hydrophilic polymer,particularly in the coating that is most proximate to the crystallinecore. Examples of hydrophilic polymeric coatings include, withoutlimitation, poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG),poly(ethylene oxide), poly(vinylpyrrolidone), poly(ethyloxazoline), orpolysaccharides or carbohydrates such as alkylcelluloses,hydroxyalkylcelluloses, hyaluronic acid, dextran, heparan sulfate,chondroitin sulfate, heparin, or alginate, or proteins such as gelatin,collagen, albumin, ovalbumin, or polyamino acids.

Additional examples of suitable polymers can be prepared from monomersselected from the following group: sugar phosphates, alkylcellulose,hydroxyalkylcelluloses, lactic acid, glycolic acid, β-propiolactone,β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxy butyric acid,α-hydroxyethyl butyric acid, α-hydroxy isovaleric acid,α-hydroxy-β-methyl valeric acid, α-hydroxy caproic acid, α-hydroxyisocaproic acid, α-hydroxy heptanic acid, α-hydroxy octanic acid,α-hydroxy decanoic acid, α-hydroxy myristic acid, α-hydroxy stearicacid, α-hydroxy lignoceric acid and β-phenol lactic acid.

Because the crystalline drug core is comprised of at least 70% by weightof the microparticles, the overall sizes of the microparticles arelargely determined by the size of the crystalline drug core. Typically,the polymeric shell has a thickness of about less than 12%, or less than5% or less than 3% of the total diameter of the microparticle. Likewise,the weight of the microparticle is also predominately the weight of thecrystalline core, resulting in a high drug loading. In preferredembodiments, the microparticle comprises 90-98% w/w of crystalline drugcore and 2-10% w/w of polymeric shell.

In various embodiments, the microparticles have a mean diameter ofbetween 50 μm and 800 μm, or a mean diameter of between 60 μm and 250μm, or a mean diameter of between 80 μm and 150 μm.

In a preferred embodiment, the mean diameter is 150 μm with a standarddeviation of less than 50% of the mean diameter. In another preferredembodiment, the mean diameter is 75 μm with a standard deviation of lessthan 50% of the mean diameter.

Methods of Forming Microparticles

Methods of forming polymeric coatings on particles are well known in theart. For example, standard techniques include solventevaporation/extraction techniques, in-water drying techniques (see,e.g., U.S. Pat. No. 4,994,281), organic phase separation techniques(see, e.g., U.S. Pat. No. 5,639,480), spray-drying techniques (see,e.g., U.S. Pat. No. 5,651,990), air suspension techniques, and dipcoating techniques.

In a most preferred form, the method of forming microparticles asdescribed in U.S. Patent Publication 2007/003619, which is fullyincorporated herein by reference. The crystalline drug core is coatedwith one or more layers of polymeric coatings, which together form thepolymeric shell. For example, in one aspect, a PVA polymeric coating canbe applied using a dip coating technique. In brief, a 1% coatingsolution of PVA in water can be formed by dissolving excess PVA in waterat 60° C. for 2 h (see, e.g., Byron and Dalby (1987), J. Pharm. Sci.76(1):65-67). Alternatively, a higher concentration PVA solution (e.g.,3-4%) can be prepared in a reflux with heating to approximately 90-100°C. After cooling, the microparticles can be added to the PVA solutionand agitated by, for example, swirling or stirring. The microparticlesare then removed from the solution by, for example, filtration on filterpaper with a mesh size appropriate to the microparticles. Optionally,vacuum-filtration can be employed to assist in drying. Untreated, PVApolymeric coatings or films are readily permeable to water andhydrophilic drugs. Heating of PVA, however, causes an increase incrystallinity and decrease of permeability of up to 500-fold withincreasing temperatures in the range of 100-250° C. for periods of 0-160hours (Byron and Dalby (1987), supra). Thus, in some embodiments, PVApolymeric coatings can be heated to temperatures between 100° C. and250° C., between 125° C. and 175° C., or between 155° C. and 170° C. forperiods between 1 sec. and 160 hours, between 1 min. and 10 hours, orbetween 5 minutes and 2 hours. Most preferably, heating is to 220° C.for one hour. Optionally, the coating process can be repeated severaltimes to build-up a thicker polymeric coating. Most preferably, 2-5coatings are applied to achieve a 5% thickness of coating.

In one embodiment, the microparticles undergo a precision heat treatmentstep at a temperature within the range of 210-230° C. for at least onehour. It is unexpectedly discovered that the level of crosslinking, andhence permeability, can be precision controlled by heating themicroparticles within this temperature range. More preferably, the heattreatment step is carried out at 220° C. for one hour. As discussed infurther detail below in connection with the dissolution characteristicsand Example 6, heat-treated microparticles at a particular temperaturerange (210-230° C.) surprisingly attain a level of crosslinking andpermeability that are capable of significantly enhancing the dissolutionhalf-life.

In Vitro Dissolution Characteristics

The structure of the microparticles makes it possible for a highlylocalized delivery system based on dissolution. Accordingly, in vitrodissolution characteristics, such as dissolution half-life arecorrelatable to the sustained release period in vivo.

It is important to recognize that dissolutions models are designed togive an accelerated dissolution as compared to in vivo release. An IVIVCthat mirrored the actual in vivo dissolution could take months tocomplete. Nevertheless, an accelerated USP type II standard dissolutionis useful to provide a qualitative comparison among various formulationsand to offer a predicator for the in vivo release behaviors.

FIG. 2 shows the effect of the microparticle structures on dissolutionrates. More specifically, FIG. 2 shows the in vitro release profiles ofuncoated fluticasone propionate powder (amorphous or very smallcrystals), uncoated fluticasone propionate crystals and coatedfluticasone propionate crystals. The dissolution profiles clearly show atrend of longer dissolution half-life and less initial burst in thecrystalline drug as compared to amorphous drug. The trend is morepronounced for the coated crystalline drug compared to the uncoatedcrystalline drug. Additional details of the dissolution conditions aredescribed in the Example sections.

The process of forming the microparticles also has a profound impact onthe dissolution characteristics. In particular, a precisionheat-treatment within a narrow temperature range (e.g., 210-230° C.)unexpectedly provides a significantly enhanced dissolution half-lifewhen compared to those of microparticles having undergone heat treatmentat temperatures outside of this range. In a dissolution test usingUnited States Pharmacopoeia Type II apparatus, wherein the dissolutionconditions are 3 milligrams of microparticles in 200 milliliters ofdissolution medium of 70% methanol and 30% of water at 25° C., thedissolution profiles of microparticles that have undergone heattreatments at 160° C., 190° C., 220° C. and 250° C. are shown in FIG.3A. Microparticles heat-treated at 220° C. have the slowest and gentlestinitial release, as compared to those of microparticles treated attemperature above or below 220° C. FIG. 3B shows the dissolutionhalf-lives of the microparticles of FIG. 3A. As shown, microparticlesheat-treated at 220° C. have a significantly longer dissolutionhalf-life (12-20 hours) than those of the other microparticles (all lessthan 8 hours).

The result indicates that precision thermal processing (i.e., heatingwithin a narrow range of temperature for a specific period of time)afford certain structural characteristics (including, e.g., degrees ofcrosslinking, crystallinity, porosity and/or permeability) that are mosteffective in enhancing the dissolution half-life, and by extension, thesustained release period.

In Vivo Release Characteristics

Preliminary animal studies indicate that corticosteroid microparticlesdescribed herein are capable of highly localized sustained releasing ofthe corticosteroid drug within a body compartment (e.g., anintra-articular space) for 2-12 months after a single injection, or moretypically, for 2-9 months, or for 3-6 months after a single injection.The results are discussed in more detail in Examples 10-13.

Even as the local concentrations exceed the EC50 of corticosteroid, theplasma concentration of the corticosteroid drug unexpectedly remainsmuch lower than the local concentrations at any given time during thesustained release period and can be below quantifiable limit after 7days. The low plasma concentration minimizes any clinically significantHPA axis suppression.

Moreover, the corticosteroid microparticles do not exhibit anysignificant initial burst (locally or systemically), unlike knowndrug-loaded microparticles.

The in vivo release characteristics confirm the release mechanism ofpseudo-zero order, by which the corticosteroid drug is released at anearly constant rate so long as a saturated solution can be maintainedwithin the polymeric shell (e.g., for more than 60 days or for more than90 days, or for more than 180 days), irrespective of the original drugloading. See also Examples 10-13.

Further, the in vivo release behaviors are correlatable to the in vitrodissolution behaviors. In particular, microparticles that have undergoneheat-treatments at different temperatures (220° C. vs. 130° C.)exhibited in vivo release behaviors that are consistent with their invitro dissolutions. See also, Examples 8 and 11.

Pharmaceutical Composition

One embodiment provides a pharmaceutical composition comprising: aplurality of microparticles, the microparticle including 1) acrystalline drug core of more than 70% by weight of the microparticle,wherein the crystalline drug core includes one or more crystals offluticasone or a pharmaceutically acceptable salt or ester thereof; and(2) a polymeric shell encapsulating the crystalline drug core, whereinthe polymeric shell is in contact but immiscible with the crystallinedrug core, wherein said composition when dissolution tested using UnitedStates Pharmacopoeia Type II apparatus exhibits a dissolution half-lifeof 12-20 hours, wherein the dissolution conditions are 3 milligrams ofmicroparticles in 200 milliliters of dissolution medium of 70% methanoland 30% of water at 25° C.

In a preferred embodiment, the crystalline drug core comprises at leastone of fluticasone, fluticasone furoate, and fluticasone propionate.

In certain embodiments, the microparticles have undergone aheat-treatment step within a temperature range of 210-230° C.

In various embodiments, the mean diameters of the microparticles are inthe range between 50 μm and 800 μm, or in the range between 60 μm and250 μm, or in the range between 80 μm and 150 μm.

In further embodiments, the crystalline drug core is more than 75%, morethan 80%, more than 85%, more than 90% or more than 95% of the totalweight of the microparticle, with the remainder of the microparticlesbeing the polymeric shell.

In various embodiments, at least 90%, at least 95%, at least 98%, or100% of the entire weight of the drug core is the drug in a crystallineform.

In preferred embodiments, the diameters of the microparticles in a givenpharmaceutical composition may be tailored or selected to suit aparticular route of administration. Thus, one embodiment provides aninjectable composition, in which more than 90% of the microparticleshave diameters in the range of 100-300 μm, which are particularlysuitable for an epidural injection. Another embodiment provides aninjectable composition comprising microparticles in which more than 90%of the microparticles have diameters in the range of 50-100 μm, whichare particularly suitable for intra-articular or intra-ocular injection.

Because the dissolution rate of the crystalline drug is related to thesize of the crystals, i.e., the smaller the crystals, the higher theinitial burst rate (see FIG. 2), it is preferred that the population ofmicroparticles in a pharmaceutical composition has a narrow sizedistribution. Thus, in one embodiment, the plurality of microparticlesin the pharmaceutical composition have a mean diameter in the range of50 μm to 300 μm and a standard deviation of less than 50% of the meandiameter.

In a preferred embodiment, the mean diameter is 150 μm with a standarddeviation of less than 50% of the mean diameter (e.g., for epiduralinjections). In another preferred embodiment, the mean diameter is 75 μmwith a standard deviation of less than 50% of the mean diameter (e.g.,for intra-articular or intra-ocular injections).

In a further embodiment, the pharmaceutical composition furthercomprises a pharmaceutically acceptable vehicle, in which the pluralityof microparticles is suspended. It is preferred that the microparticlesof corticosteroid are mixed with the vehicle immediately prior toinjection, so there is no time for the corticosteroid to dissolve intothe vehicle and there is no or substantially no initial burst of drugprior to injection.

Unit Dosage Form

A unit dosage form is a pharmaceutical composition (including all theembodiments as described above) having a predetermined quantity ofcorticosteroid microparticles which, after a single injection, providessustain release of the corticosteroid for a specified period. Thequantity of the corticosteroid microparticles in a unit dosage willdepend upon several factors including the routes of administration(intra-articular, intra-epidural, or intra-ocular), the body weight andthe age of the patient, the severity of inflammation or pain, or therisk of potential side effects considering the general health status ofthe person to be treated.

Advantageously, because the corticosteroid microparticles describedherein are capable of near zero-order release with little initial burst,the initial loading the drug in the unit dosage form can be rationallydesigned according to the desired sustained release period.

Thus, one embodiment provides an injectable unit dosage form of acorticosteroid for injecting into a body compartment, the injectableunit dosage form comprising: a plurality of microparticles, themicroparticle including (1) a crystalline drug core of more than 70% byweight of the microparticle; and (2) a polymeric shell encapsulating thecrystalline drug core, wherein the crystalline drug core includes one ormore crystals of a corticosteroid selected from fluticasone, fluticasonefuroate, and fluticasone propionate, and the polymeric shell is incontact but immiscible with the crystalline drug core, wherein theinjectable dosage form is capable of sustained-release of thecorticosteroid for a period of 2-20 months while maintaining a minimumtherapeutically effective concentration of the corticosteroid within thebody compartment.

In a further embodiment, the sustained release period is 2-9 months.

In a further embodiment, the sustained release period is 3-6 months.

In other embodiment, the plasma concentration of the corticosteroid isbelow quantifiable level after 7 days.

In various embodiments, the unit dosage form comprises 0.5-20 mg ofcorticosteroid. In other embodiments, the unit dosage form comprises3-20 mg of corticosteroid.

In various embodiments, the unit dosage form further comprises apharmaceutically acceptable vehicle. Preferably, the vehicle is combinedwith the corticosteroid microparticles immediately before injection toavoid dissolution of the drug into the vehicle. Advantageously, becauseof the lack of initial burst, any dissolution of the corticosteroid intothe vehicle during normal handling time in preparation for an injectionis insignificant. In contrast, many known drug-loaded sustained releaseformulations are capable of saturating the vehicle during handling timedue to an initial burst.

Methods of Using and Routes of Administration

The pharmaceutical compositions and dosage forms described herein aredesigned to be injected into a body compartment for highly localized,sustained release of corticosteroid. The body compartment typicallycontains soft tissue and/or fluid within an enclosure or semi-enclosure.The injection is directed to the soft tissue or the fluid, into whichthe corticosteroid microparticles are released. When needed, theinjection can be guided by an imaging system such as an ultrasonic orX-ray device.

In one embodiment, the injection is administered intra-articularly forsustained-release of a corticosteroid in the synovium or synovial fluid.

In another embodiment, the injection is administered into an epiduralspace for sustained-release of a corticosteroid.

In a further embodiment, the injection is administered intra-ocularly,or intra-vitreously for sustained-release of a corticosteroid in thevitreous humour.

In a further embodiment, the injection is administered to a surgicallycreated pocket or a natural space near an implant for sustained-releaseof a corticosteroid therein for reducing pain and/or inflammationassociated with capsule constriction (e.g., following implant) or keloidscar formation.

Diseases that May be Treated Using the Formulations of this Disclosure

Various embodiments provide long-acting treatments or therapies forreducing inflammation and/or pain. Although these embodiments areexemplified with reference to treat joint pain associated withosteoarthritis, rheumatoid arthritis and other joint disorders, itshould not be inferred that the disclosure is only for these uses.Rather, it is contemplated that embodiments of the present disclosurewill be useful for treating other forms of pain and/or inflammation byadministration into articular and peri-articular spaces, epidural space,vitreous humour of the eye, or space near an implant having scar tissueformation.

Thus, the diseases and conditions that may be treated by intra-articularinjection of the pharmaceutical composition and unit dosage formdescribed herein include, without limitation, osteoarthritis, rheumatoidarthritis or injury induced arthritis, Lupus, traumatic arthritis,polymyalgia rheumatica, post-operative joint pain, facet jointdisease/inflammation, tensynovitis, bursitis, fasciitis, ankylosingspondylitis.

In other embodiments, the diseases and conditions that may be treated byan injection to the epidural space include, without limitation, spinaldisc protrusion, spinal nerve inflammation in cervical, thoracic orlumbar, chronic low back pain from nerve root compression.

In other embodiments, the diseases and conditions that may be treated byan intra-ocular or intra-vitreous injection include, without limitation,diabetic macular edema and uveitis.

In other embodiments, the diseases and conditions that may be treated byan injection into a space near an implant having scar tissue formationfor releasing pain and inflammation are related to recurrent capsularcontractions (e.g., breast implant) and for keloid scarring control.

Thus, one embodiment provides a method of treating inflammation ormanaging pain in a body compartment of a patient in need thereof,comprising injecting to the body compartment a therapeutically effectiveamount of pharmaceutical composition having a plurality ofmicroparticles, the microparticle including 1) a crystalline drug coreof more than 70% by weight of the microparticle, wherein the crystallinedrug core includes one or more crystals of fluticasone or apharmaceutically acceptable salt or ester thereof; and (2) a polymericshell encapsulating the crystalline drug core, wherein the polymericshell is in contact but immiscible with the crystalline drug core.

In a preferred embodiment, the crystalline drug core comprises at leastone of fluticasone, fluticasone furoate, and fluticasone propionate.

In various embodiments, the microparticles have undergone aheat-treatment step within a temperature range of 210-230° C.

In various embodiments, the mean diameters of the microparticles are inthe range between 50 μm and 800 μm, or in the range between 60 μm and250 μm, or in the range between 80 μm and 150 μm.

In preferred embodiments, the diameters of the microparticles in a givenpharmaceutical composition may be tailored or selected to suit aparticular route of administration. Thus, one embodiment provides aninjectable composition, in which more than 90% of the microparticleshave diameters in the range of 100-300 μm, which are particularlysuitable for an epidural injection. Another embodiment provides aninjectable composition comprising microparticles in which more than 90%of the microparticles have diameters in the range of 50-100 μm, whichare particularly suitable for intra-articular or intra-ocular injection.

In further embodiments, the crystalline drug core is comprised of morethan 75%, more than 80%, more than 85%, more than 90% or more than 95%of the total weight of the microparticle, while the remainder being thepolymeric shell.

In various embodiments, at least 90%, at least 95%, at least 98%, or100% of the entire weight of the drug core is the drug in a crystallineform.

In certain embodiments, said composition when dissolution tested usingUnited States Pharmacopoeia Type II apparatus exhibits a dissolutionhalf-life of 12-20 hours, wherein the dissolution conditions are 3milligrams of microparticles in 200 milliliters of dissolution medium of70% methanol and 30% of water at 25° C.

In other embodiments, said composition when dissolution tested usingUnited States Pharmacopoeia Type II apparatus exhibits a dissolutionhalf-life of 12-20 hours, wherein the dissolution conditions are 3milligrams of microparticles in 200 milliliters of dissolution medium of70% methanol and 30% of water at 25° C.

A specific embodiment further provides a method of decreasinginflammation and pain in a patient comprising administering to thepatient in need thereof, via intra-articular injection, atherapeutically effective amount of a pharmaceutical preparation forsustained release of a corticosteroid comprising a multiplicity ofcoated microparticles, said coated microparticles having a mean diameterof 50 μm and 350 μm and wherein the microparticles are particlescomprised of greater than 70% corticosteroid by weight.

Another embodiment provides a method of treating inflammation ormanaging pain in a body compartment of a patient in need thereof,comprising injecting to the body compartment a single injection of aunit dosage form having a plurality of microparticles, the microparticleincluding (1) a crystalline drug core of more than 70% by weight of themicroparticle; and (2) a polymeric shell encapsulating the crystallinedrug core, wherein the crystalline drug core includes one or morecrystals of a corticosteroid selected from fluticasone, fluticasonefuroate, and fluticasone propionate, and the polymeric shell is incontact but immiscible with the crystalline drug core, wherein theinjectable dosage form is capable of sustained-release of thecorticosteroid for a period of 2-12 months while maintaining a minimumtherapeutically effective concentration of the corticosteroid within thebody compartment.

Additional specific embodiments include:

-   -   said microparticles have a mean diameter of between 50 μm and        800 μm.    -   said microparticles have a mean diameter of between 60 μm and        250 μm.    -   said microparticles have a mean diameter of between 80 μm and        150 μm.    -   the corticosteroid is selected from the group consisting of        fluticasone, fluticasone furoate, and fluticasone propionate.    -   the corticosteroid is a pharmaceutically acceptable ester        prodrug of fluticasone (fluticasone propionate).    -   said preparation is administered at a site permitting direct        interaction between said corticosteroid and an affected joint of        said patient.    -   sustained release refers to at least three months.    -   wherein inflammation and pain is arthritic joint pain.    -   wherein said pharmaceutical preparation for sustained release        comprises large particles of substantially pure corticosteroid        coated with at least one biocompatible or bio-erodible polymer.    -   which reduces or eliminates an initial corticosteroid drug        burst.    -   the polymer comprises at least one of polylactic acid, polyvinyl        alcohol and Parylene™    -   the systemic levels of fluticasone administered in the method as        described herein produce no clinically significant HPA axis        suppression.    -   inflammation and pain in a patient is due to at least one of        osteoarthritis, rheumatoid arthritis or injury induced        arthritis.    -   there is at or near consistent and sustained release of a        corticosteroid.    -   the disease progression is slowed or halted due to the        maintaining of the constant low level of steroid in the joint        space    -   the particles of corticosteroid are mixed with the vehicle        immediately prior to injection, so there is no time for the        corticosteroid to dissolve into the vehicle and there is no or        substantially no initial burst of drug.    -   the present method has fewer systemic side effects than other        therapies

Within the scope of the present disclosure, the corticosteroid isselected from the group consisting of fluticasone, fluticasone furoate,and fluticasone propionate. More preferably:

-   -   the corticosteroid is fluticasone propionate.    -   diffusion of said corticosteroid across said first polymeric        coating exhibits pseudo-zero-order kinetics during said        sustained-release period.    -   said first polymeric coating is not degraded until AFTER a        sustained release period (which is a point of differentiation as        compared to other sustained release formulations)    -   said first polymeric coating maintains structural integrity        during said sustained-release period.    -   said microparticles have a maximum dimension between 50 μm and        250 μm.    -   said microparticles have a maximum dimension between 50 μm and        150 μm.    -   said corticosteroid is substantially insoluble in said coating        solution.    -   said corticosteroid is hydrophobic and said first coating        solution is hydrophilic.    -   The polymeric shell comprises one or more polymeric coatings        that are the same or different and may comprise a polymer or        co-polymer including at least one monomer selected from the        group consisting of sugar phosphates, alkylcellulose,        hydroxyalkylcelluloses, lactic acid, glycolic acid,        β-propiolactone, β-butyrolactone, γ-butyrolactone,        pivalolactone, α-hydroxy butyric acid, α-hydroxyethyl butyric        acid, α-hydroxy isovaleric acid, α-hydroxy-β-methyl valeric        acid, α-hydroxy caproic acid, α-hydroxy isocaproic acid,        α-hydroxy heptanic acid, α-hydroxy octanic acid, α-hydroxy        decanoic acid, α-hydroxy myristic acid, α-hydroxy stearic acid,        α-hydroxy lignoceric acid, β-phenol lactic acid, ethylene vinyl        acetate, and vinyl alcohol.    -   the polymeric coating is applied to said core particles by an        air suspension technique.    -   said polymeric coating is applied to said core particles by a        dip coating technique.

These and other changes can be made to the present systems, methods andarticles in light of the above description. In general, in the followingclaims, the terms used should not be construed to limit the disclosureto the specific embodiments disclosed in the specification and theclaims, but should be construed to include all possible embodimentsalong with the full scope of equivalents to which such claims areentitled. Accordingly, the disclosure is not limited by the disclosure,but instead its scope is to be determined entirely by the followingclaims.

EXAMPLES Example 1 General Procedure for Preparing Crystalline Drug Core

To fluticasone propionate (FP) powder (1 g), methanol (100 mL) is addedand the suspension heated with stirring until a clear solution isobtained. The flask is left at room temperature over-night resulting inthe formation of needle-shaped crystals. The crystals are collectedusing a Buchner funnel and thoroughly oven-dried at 40-50° C. for 2 h.The dry FP particles are added to an 80-170 μm mesh sieve along with amonolayer of glass beads. A 30-60 μm mesh sieve is added below the sievecontaining the FP particles and beads, followed by shaking for 3-4 min.The 80-170 μm mesh sieve is replaced with a clean 80-170 μm mesh sieve,a 2000 μm mesh sieve added to the top (optional), and the sieve stackattached to a Buchner funnel. The content of the 80-170 μm mesh sievecontaining the FP particles and beads is gently poured into the 2000 μmmesh sieve to collect the glass beads and washed with deionized water(DI-H₂O) under suction. The 2000 μm mesh sieve is removed and thecontent of the 80-150 μm mesh sieve washed with DI-H₂O under suction. Atotal of 200-300 mL of DI-H₂O typically is used. Alternatively, thecontent of the sieves may be washed with TWEEN-80 (0.1% w/v) beforewashing with water, or the glass beads are replaced by gentle grindingusing a glass rod in a 212 μm mesh sieve. The content of the 80-170 μmand 30-60 μm mesh sieves is separately dried at 40° C. and the drymaterial combined for polymer coating.

Example 2 Size Distribution of Crystalline Drug Core

1 gram of fluticasone propionate (FP) powder (CAS 80474-14-2) wasdissolved in 100 mL of ACS-grade methanol over a hot plate. The finalsolution was clear. This solution was cooled and allowed to rest for 24h at room temperature. The resulting crystals were filtered, sieved andcollected below 180 μm screens (−180 μm), cleaned with 0.1% TWEEN-80aqueous solution, and washed twice with distilled water and dried at 40°C. for 3 h. 940 mg of fluticasone propionate crystals (94% yield) wereobtained using this procedure. FIGS. 4A and 4B show the mean particlesizes obtained and size distributions.

FIG. 4A is a graph representing the particle size distribution offluticasone propionate monodisperse distribution with mean particle sizeof ca. 110 μM, and the standard deviation is ca. 41 μM. Particles ofthese sizes can be injected easily through 23 g needle (internaldiameter 320 μM)

As a comparison, FIG. 4B is a graph representing the particle sizedistribution of Traimcinolone Acetonide (Kenalog™). The mean particlesize is ca. 20 μM. There is a relatively wide distribution with a secondpeak at ca. 1 μM. The standard deviation is about 13 μM. These smallparticles contribute to the burst effect seen with this type offormulation common in the prior art. See also FIG. 6.

Example 3 General Procedure for Coating Crystalline Drug Core

The dry FP crystals prepared according Example 1 are coated withpolyvinyl alcohol (PVA, 2% w/v in 25% v/v isopropyl alcohol in DI-H₂O)in a model VFC-LAB Micro benchtop fluidized bed coater system (VectorCorporation) using the following range of parameters:

air flow, 50-60 L min⁻¹;

nozzle air, 5.0-25 psi;

pump speed, 10-35 rpm;

inlet temperature, 99° C.;

exhaust temperature, 35-40° C.;

spray on/off cycle: 0.1/0.3 min.

The PVA content is periodically measured by quantitative ¹H nuclearmagnetic resonance (NMR) spectroscopy by comparing the relative signalintensities of the FP and PVA resonances in the drug product tocorresponding signals from calibration standards (See Example 3). Atarget final PVA concentration in the drug product is in the range of0.1-20% w/w, or preferably 2-10% w/w. Coating of the particles iscontinued until the desired amount of PVA has been achieved. The coatedparticles are then dried in an oven at 40° C. for 1 h. The dry, coatedparticles are sieved in a sieve stack defined by 150 μm mesh and 53 μmmesh sieves.

Example 4

NMR Analysis for Determining Drug Content in Microparticles

NMR analysis was used to determine the amounts of the drug core and thepolymeric shell in microparticles by calibrating with samples of knownquantity of the pure drug.

The NMR system includes a Bruker Spectrospin 300 MHz magnet, BrukerB-ACS 120 autosampler, Bruker Avance II 300 console, and a Bruker BBO300 MHz S1 5 mm with Z gradient probe. A calibration curve was preparedusing five samples of known fluticasone propionate, and PVAconcentrations made in NMR grade d6-DMSO. Proton (1H) NMR was run on twosamples: the first containing only pure fluticasone propionate and thesecond containing PVA-coated fluticasone. Each sample was loadedmanually and spun at 20 Hz inside the magnet. The probe was tuned andmatched for proton (1H) NMR. The magnet was shimmed manually with thefirst sample in the magnet. Each sample was integrated for 1.5 hourswith 1024 scans. Fluticasone peaks were integrated from 5.5 to 6.35 ppm,and the PVA peak was integrated from 4.15 to 4.7 ppm (see FIG. 5). Usingthis method, the finished coated fluticasone particles were determinedto contain 2.1% PVA total weight of coated particles. Assuming sphericalparticle shape and mean particle diameter of 100 μm, this represents acoating thickness of ca. 7 μm.

Example 5 In Vitro Dissolution Analysis

To each vessel (1000 mL capacity) of a USP Type II dissolution system isadded the dissolution medium and 3 mg of PVA-coated FP particles. Thedissolution medium typically consists of 5-90% v/v of an alcohol-watermixture, where the alcohol can be methanol, ethanol, and isopropanol.The volume of dissolution medium used is in the 50-750 mL range. Thetemperature of the dissolution medium is maintained either at roomtemperature or at a temperature in the 5-45° C. range. Aliquots areremoved from the dissolution medium at regular, predetermined timepoints and the samples are stored for subsequent analysis, such as withUV-visible absorption spectroscopy or high performance liquidchromatography.

A specific set of dissolution conditions is as follows:

drug for dissolution: 3 mg PVA-coated FP particles;

dissolution medium: 200 ml of 70% v/v ethanol and 30% v/v water;

dissolution temperature: 25° C.

Example 6 Thermal Processing and Effects on Dissolutions

The coated microparticles prepared according to Example 2 were thermalprocessed, i.e., heat treated for a specific period of time.Specifically, the interior of a borosilicate Petri dish was lined withaluminum foil and a monolayer of PVA-coated FP particles was spread. Thedish was covered with perforated aluminum foil. An oven was pre-heatedto the desired set-point and the samples were heat-treated for apre-determined amount of time. The temperature set-point were 160° C.,190° C., 220° C. and 250° C.

FIG. 3A shows the dissolution profiles of microparticles havingundergone heat treatments at the above temperatures. The dissolutionconditions are as follows: 3 mg of PVA-coated FP microparticles weredissolved in a dissolution medium of 200 ml of 70% v/v ethanol and 30%v/v water at 25° C. The resulting concentration-time data are analyzed(e.g., one phase decay model) to afford the dissolution half-life (shownin FIG. 3B).

As shown in FIG. 3A, microparticles heat-treated at 220° C. have theslowest and gentlest initial release, as compared to those ofmicroparticles treated at temperature above or below 220° C.

FIG. 3B shows that the dissolution half-lives of the microparticles ofFIG. 3A. As shown, microparticles heat-treated at 220° C. have asignificant longer dissolution half-life (12-20 hours) that those of theother microparticles (all less than 8 hours).

Example 7 Sustained Release (SR) Formulations for Animal Study (Sheep)

Dry FP crystals were prepared according to Example 1 and were coatedwith polyvinyl alcohol (PVA, 2% w/v in 25% v/v isopropyl alcohol inDI-H₂O) in a model VFC-LAB Micro bench top fluidized bed coater system(Vector Corporation) using the following range of parameters: air flow,50-60 L/min; nozzle air, 23 psi; pump speed, 15 rpm; inlet temperature,99° C.; exhaust temperature, 35-40° C.; spray on/off cycle: 0.1/0.3 min.

The resulting microparticles were then heat-treated at 130° C. for 3hours.

The microparticles have mean diameters in the range of 60-150 μm. ThePVA content of the resulting microparticles was 2.4% as analyzed by NMRanalysis according to the method described in Example 4.

Example 8 Sustained Release (SR) Formulations for Animal Study (Dog)

Dry FP crystals were prepared according to the above procedures and werecoated with polyvinyl alcohol (PVA, 2% w/v in 25% v/v isopropyl alcoholin DI-H₂O) in a model VFC-LAB Micro benchtop fluidized bed coater system(Vector Corporation) using the following range of parameters: air flow,50-60 L/min; nozzle air, 8.0 psi; pump speed, 25 rpm; inlet temperature,99° C.; exhaust temperature, 35-40° C.; spray on/off cycle: 0.1/0.3 min.

The resulting microparticles were then heat-treated at 220° C. for 1.5hours.

The microparticles have mean diameters in the range of 60-150 μm. ThePVA content of the resulting microparticles was 4.6% as analyzed by NMRanalysis according to the method described in Example 4.

FIG. 6 shows the dissolutions profiles of the microparticles prepared byExample 8 compared to the microparticles prepared by Example 7. Inaddition, FIG. 6 further shows the dissolution profiles of anothercorticosteroid (triamcinolone acetonide) and fluticasone propionatepowder (uncoated, non-crystalline or very small, less than 10 μmcrystals). Both coated FP microparticles (Examples 7 and 8) exhibit muchlonger dissolution half-lives and less initial bursts than the FP powderand triamcinolone acetonide. In addition, microparticles that have beenheat-treated at 220° C. are shown to have even longer dissolutionhalf-life than microparticles similarly prepared but heat-treated at130° C. (Example 7).

The dissolution conditions were as follows:

drug for dissolution: 3 mg PVA-coated FP particles

dissolution medium: 200 ml of 70% v/v ethanol and 30% v/v water;

dissolution temperature: 25° C.

Example 9 Formulation of Suspension/Injectability

Optimized suspension formulations of coated particles were obtainedusing an iterative process, whereby different suspension solutions atvarying concentrations were assessed for their ability to keep coatedparticles in suspension. The most homogeneously distributed formulationswere then injected through needle sizes ranging from 18 to 25 gauge.Particle transfer efficiency was measured by HPLC. A 1% CMC solutionprovided the maximum suspension and a 23 gauge needle provided adequateinjection efficiency.

Sterility.

Polymer-coated fluticasone particles were steam-sterilized (122° C., 16psi, 30 min) in amber vials. The sterilization process did not affectthe chemical composition of the formulation according to ¹H NMRspectroscopy and HPLC analysis. See FIG. 5. In vitro studies in 500 mLUSP Type II systems confirmed that the sterile material had the samefluticasone release profile as the same material prior to autoclaving.

Example 10 In Vivo Pharmacokinetic (PK) Studies (Sheep)

In a non-GLP exploratory study, the local toxicity and drugconcentration levels were evaluated for 3 months in sheep (n=4) after asingle intra-articular injection into the left stifle joint using a 23 Gneedle of a tuberculin syringe. The injectable dosage form was 0.5 mL of20 mg extended release fluticasone propionate (EP-104) preparedaccording to Example 7.

Clinical observations were performed throughout the study, andhistopathology was performed at the end of the study to evaluate localtoxicity. To evaluate fluticasone propionate concentration levels intreated knees, synovial fluid samples were collected at designated timepoints. Blood was collected throughout the study to determine plasmaconcentration levels. Plasma fluticasone levels were measured byHPLC-MS. Mistry N, et al. Characterisation of impurities in bulk drugbatches of fluticasone propionate using directly coupled HPLC-NMRspectroscopy and HPLC-MS. Journal of Pharmaceutical and BiomedicalAnalysis 16(4):697-705, 1997. Mortality, morbidity, and body weightswere also evaluated.

There were no changes during clinical observations, and nohistopathologic changes occurred in any of the knees after 3 months.There was no mortality or morbidity, and sheep gained weight throughoutthe study.

Fluticasone propionate concentrations were detected in synovial fluid at3 months (n=4; 11.51, 9.39, 13.22, and 18.89 ng/mL). Plasmaconcentration levels were less and declined at a greater rate than thoseof synovial fluid Fluticasone propionate concentrations in plasma werebelow quantifiable limits (BQL) at 0 or below 0.3 ng/mL beginning at Day70. Plasma and synovial fluid concentrations throughout the study areprovided in FIG. 7.

Of note is an absence of burst and sustained local concentrationsachieved for the duration of the experiment. The reported EC50 forfluticasone propionate is 7-30 pg/ml. Möllmann H, et al. Pharmacokineticand pharmacodynamic evaluation of fluticasone propionate after inhaledadministration, European journal of clinical pharmacology February;53(6):459-67, 1998. Significantly, after 90 days, the localconcentration of FP in the synovial fluid remained considerable amount(n=4; 11.51, 9.39, 13.22, and 18.89 ng/mL) and above the EC50 level,while the plasma concentration was no longer detectable (the plasmaconcentration became BQL at day 70).

As a comparison, the release of triamcinolone hexacetonide (40 mg) fromhuman subjects is also plotted in FIG. 7. Derendorf H, et al.Pharmacokinetics and pharmacodynamics of glucocorticoid suspensionsafter intra-articular administration. Clinical Pharmacology andTherapeutics March; 39(3):313-7 (1986). As shown, triamcinolonehexacetonide release shows a significant initial burst followed by rapiddecline. The duration of release is significant shorter than that of thecoated FP microparticles described herein, despite having a much higherinitial dose.

The shape of the PK curve of the corticosteroid microparticles issubstantially different from that of the triamcinolone hexacetonide. Theslow rise and near constant release over a period of 60 days confirmsthe release mechanism of pseudo-zero order, by which the corticosteroiddrug is released at a nearly constant rate so long as a saturatedsolution can be maintained within the polymeric shell (e.g., for 60days), irrespective of the original drug loading.

The animals were euthanized on day 90 and the joints excised and sentfor histology. There were no safety or toxicity issues noted on clinicalexamination. Histological examination of the injected joints showed noabnormalities (FIGS. 8A, 8B, and 8C).

Example 11 In Vivo Pharmacokinetic (PK) Studies (Dogs)

Extended release fluticasone propionate formulation (EP-104IAR) wasprepared according to Example 8. The in vivo release characteristicswere evaluated in the knee of Beagle dogs (n=32) during a 60-day study.Two groups of 16 male and female dogs were evaluated. Group 1 (n=8 malesand 8 females) were administered a target dose of 0.6 mg EP-104IAR byintra-articular injection (the low dose group). Group 2 was administereda target dose of 12 mg EP-104IAR by intra-articular injection (the highdose group).

Synovial fluid and plasma were collected at 7, 29, 46, and 60 days afterinjection, and cartilage tissue drug concentrations and microscopicchanges were also evaluated at these time points. Mortality checks,clinical observations, and body weight measurements were performed.Blood was collected for plasma bioanalysis from all surviving animals atpre-dose, and on Days 3, 5, and 7; and twice weekly thereafter untilnecropsy (including the day of necropsy). Two animals/sex from eachgroup were euthanized on Day 7, 29, 46 or 60. Prior to necropsy,synovial fluid was collected for bioanalysis.

Results:

In the low dose group, there were no measurable concentrations of freefluticasone propionate in plasma at any of the sampling time points,indicating the drug remained in the joint. See FIG. 9.

In the high dose group, measurable but low plasma concentrationsoccurred on Day 3 after injection and ranged from 0.2 to 0.5 ng/mL. Onthe other hand, local concentrations of the drug in the synovial fluidand tissue were significantly higher throughout the entire period of thestudy. See FIG. 10.

The highest concentrations of fluticasone propionate in synovial fluidgenerally occurred on Day 7 in both dose groups and ranged from 3 to 25ng/mL in the low dose group (FIG. 9) and 179 to 855 ng/mL in the highdose group (FIG. 10). In the low dose group, measurable fluticasonepropionate concentrations in synovial fluid were detected at Day 60, butconcentrations were below the limit of quantification (1.0 ng/mL) atthis collection time point. Fluticasone propionate concentrations insynovial fluid of high dose animals at Day 60 were 97 to 209 ng/mL.

Example 12 Comparative Results—Sheep Vs. Dog Studies

FIG. 6 demonstrates the impact on dissolution characteristics by athermal processing step during the microparticle formation. Inparticular, microparticles that have undergone a precision thermalprocessing step (220° C. for 1.5 hours) exhibited a significantly longerdissolution half-life than that of microparticles that have undergone athermal processing step at a much lower temperature (130° C. for 3hours). The result indicates that the precision thermal processing stepat 220° C. has caused certain structural changes in the polymeric shellthat in turn altered its permeation characteristics.

Microparticles that have undergone different thermal processing stepswere used in the sheep study (heat-treated at 130° C.) and dog study(heat-treated at 220° C.) and their in vivo sustained release behaviorswere discussed in Examples 9 and 10, respectively.

FIG. 11 shows the plasma concentrations measured in the sheep study ascompared to those in the dog study. As shown, the plasma concentrationsin the sheep study exhibited much higher concentrations after 3 days,when compared to those in the dog study, despite the fact that the sheepreceived a substantially lower dose (0.25 mg/kg) than the dogs (1.2mg/kg). Moreover, the plasma concentrations in the dogs were largelyconstant before they became undetectable. In contrast, the plasmaconcentrations in the sheep exhibited more variations over the releaseperiod. The results indicate that the thermal processing step during themicroparticle formation had a significantly impact on the releasebehaviors in vivo, much like it did on the dissolution behaviors invitro (See Example 8).

Example 13 Lack of Initial Burst

Fluticasone propionate microparticles were prepared according to Example8. Microparticles having mean diameters in the range of 50-100 μm wereused to study the plasma pharmacokinetic (PK) in the first two daysfollowing injection. Two groups of dogs (n=3 per group) were injectedwith a 2 mg dose (low dose) and a 60 mg dose (high dose), respectively.

Most sustained release formulations are expected to exhibit an initialburst or a peak in the plasma within the first 48 hours followingdosing. Unexpectedly, however, the FP sustained release formationaccording to an embodiment of this disclosure shows no initial burst.FIG. 12 shows a complete absence of initial burst or peak in the first 2days in the high dose group and all samples were below limit ofquantification (albeit detectable). In the low dose group only a singlesample was detectable, but was below quantification. Accordingly, thesustained release formulations described herein are capable of highlylocalized delivery of a corticosteroid (e.g., fluticasone propionate)while keeping the systemic corticosteroid below the level that mayresult in any clinically significant HPA axis suppression.Significantly, the complete absence of an initial burst in even the highdose group indicates that the in vivo release is following a zero-orderor pseudo-zero order pattern.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet, are incorporated herein byreference, in their entirety.

We claim:
 1. A pharmaceutical composition, comprising: a plurality ofmicroparticles, each microparticle including: (1) a crystalline drugcore of more than 70% by weight of the microparticle, each crystallinedrug core comprising 100% of fluticasone propionate; and (2) a polymericshell encapsulating the crystalline drug core, the polymeric shell beingin contact but immiscible with the crystalline drug core, and thepolymeric shell comprising polyvinyl alcohol (PVA), wherein thepolymeric shell is heat treated within a temperature range of 210-230°C. for at least one hour, wherein, when dissolution tested using UnitedStates Pharmacopoeia Type II apparatus, said microparticles releasedissolved fluticasone or a pharmaceutically acceptable salt or esterthereof at a dissolution half-life of 12-20 hours, wherein thedissolution conditions are: 3 milligrams of microparticles in 200milliliters of dissolution medium of 70% v/v methanol and 30% v/v ofwater at 25° C., and wherein the plurality of microparticles have a meandiameter in the range of 80 μm to 150 μm and a standard deviation ofless than 50% of the mean diameter.
 2. The pharmaceutical composition ofclaim 1 wherein the plurality of microparticles have a mean diameter of80 μm and a standard deviation of less than 50% of the mean diameter. 3.The pharmaceutical composition of claim 1 wherein the plurality ofmicroparticles have a mean diameter of 150 μm and a standard deviationof less than 50% of the mean diameter.
 4. The pharmaceutical compositionof claim 1 wherein each microparticle comprises 90-98% w/w ofcrystalline drug core and 2-10% w/w of polymeric shell.
 5. Apharmaceutical composition, comprising: a plurality of microparticles,each microparticle including: (1) a crystalline drug core of more than70% by weight of each microparticle, the crystalline drug corecomprising 100% of fluticasone propionate; and (2) a polymeric shellencapsulating the crystalline drug core, the polymeric shell being incontact but immiscible with the crystalline drug core, and the polymericshell comprising polyvinyl alcohol (PVA), wherein the polymeric shell isheat treated within a temperature range of 210-230 C for at least onehour, wherein, when dissolution tested using United States PharmacopoeiaType II apparatus, said microparticles release dissolved fluticasone ora pharmaceutically acceptable salt or ester thereof at a dissolutionhalf-life of 12-20 hours, wherein the dissolution conditions are: 3milligrams of microparticles in 200 milliliters of dissolution medium of70% v/v methanol and 30% v/v of water at 25° C., and wherein themicroparticles have a mean diameter in the range of 50-100 μm.
 6. Thepharmaceutical composition of claim 5 wherein each microparticlecomprises 90-98% w/w of crystalline drug core and 2-10% w/w of polymericshell.
 7. A pharmaceutical composition, comprising: a plurality ofmicroparticles, each microparticle including: (1) a crystalline drugcore of more than 70% by weight of each microparticle, the crystallinedrug core comprising 100% of fluticasone propionate; and (2) a polymericshell encapsulating the crystalline drug core, the polymeric shell beingin contact but immiscible with the crystalline drug core and thepolymeric shell comprising polyvinyl alcohol (PVA), wherein, whendissolution tested using United States Pharmacopoeia Type II apparatus,said microparticles release dissolved fluticasone or a pharmaceuticallyacceptable salt or ester thereof at a dissolution half-life of 12-20hours, wherein the dissolution conditions are: 3 milligrams ofmicroparticles in 200 milliliters of dissolution medium of 70% v/vmethanol and 30% v/v of water at 25° C., wherein more than 90% of themicroparticles have diameters in the range of 50-100 μm, and wherein thepolymeric shell is heat treated within a temperature range of 210-230°C. for at least one hour.
 8. The pharmaceutical composition of claim 7wherein each microparticle comprises 90-98% w/w of crystalline drug coreand 2-10% w/w of polymeric shell.